The efficacy of many pharmaceutical agents is predicated on their ability to proceed to the selected target sites and remain there in effective concentrations for sufficient periods of time to accomplish the desired therapeutic or diagnostic purpose. Difficulty in achieving efficacy may be exacerbated by the location and environment of the target site as well as by the inherent physical characteristics of the compound administered. For example, drug delivery via routes that are subject to repeated drainage or flushing as part of the bodies natural physiological functions offer significant impediments to the effective administration of pharmaceutical agents. In this respect, delivery and retention problems are often encountered when administering compounds through the respiratory or gastrointestinal tracts. Repeated administration of fairly large doses are often required to compensate for the amount of drug washed away and to maintain an effective dosing regimen when employing such routes. Moreover, the molecular properties of the pharmaceutical compound may impair the absorption through a given delivery route, thereby resulting in a substantial reduction in efficacy. This is particularly true of lipophilic compounds that are not soluble in aqueous environments. For instance, insoluble particulates are known to be subject to phagocytosis and pinocytosis, resulting in the accelerated removal of the compound from the target site. Such reductions in delivery and retention time complicate dosing regimes, waste pharmaceutical resources and generally reduce the overall efficacy of the administered drug.
Unlike many hydrophilic compounds, the delivery of lipophilic drugs by conventional means has been and continues to be problematic. Unfortunately, a number of the most promising therapeutic and diagnostic agents currently under development are bulky polycyclic molecules that tend to be relatively insoluble in water. The substantial physical size of these compounds, coupled with the intrinsic lipophilicity of their molecular structure, has severely limited their use in practical pharmaceutical applications. For instance, the oral administration of lipophilic agents using conventional tablets and capsules suffers the disadvantage of a variable rate of absorption of the administered drug and depends on factors such as the presence or absence of food, the Ph of gastrointestinal fluids and gastric emptying rates. Moreover, the insolubility of large lipophilic particulates tends to reduce delivery rates as little drug dissolves in the gastrointestinal liquid and crosses the epithelial barrier before it is excreted. Finally, the degradation of labile drugs by gastric fluids and drug metabolizing enzymes may reduce the drug bioavailability to the point of therapeutic failure (Prescott, L. F., in Novel Drug Delivery and its Therapeutic Application, John Wiley & Sons, New York, 1989, pp. 3-4).
Other delivery routes fare little better when lipophilic compounds are administered using conventional delivery vehicles. The parenteral administration of these water insoluble drugs requires that they be formulated in the form of oil in water emulsions or that they be solubilized into a water miscible phase. This suffers drawbacks associated with the formulation of a suitably stable dosage form that can be delivered by this route; such formulations often contain surfactant systems which, by themselves, may cause toxic side effects. For example, the current method used for the intravenous administration of the highly lipophilic cancer drug Taxol involves the use of a polyoxyethylated castor oil vehicle that has been associated with hypersensitivity reactions including dyspnea, bronchospasm, urticaria, and hypotension (Rowinsky, E. K. and Donehower, R. C., New Eng. J. Med., 1995, 332, 1004). In addition, the intravenous administration of drugs such as Taxol, which exhibit high systemic toxicities, severely limits their therapeutic capacity (Balasubramanian, S. V. and Straubinger, R. M., Biochemistry, 1994, 33, 8941). Thus, despite encouraging results with existing delivery other reference systems, the inherently low bioavailability of these lipophilic compounds at the target site due to inefficient or toxic delivery systems substantially reduces their efficacy.
In spite of the difficulties associated with the delivery of lipophilic drugs, the potential advantages in developing methods to do so are great. Extensive work has been done to show that the membrane permeability, bioavailability and efficacy of drugs often increases with increasing lipophilicity (Banker G. S. and Rhodes, C. T. in "Modern Pharmaceutics", Marcel Dekker, Inc., New York, 1979, pp. 31-49; Hughes, P. M. and Mitra, A. K., J. Ocul. Pharmac., 1993, 9, 299; Yokogawa, K., Nakashima, E., Ishizaki, J., Maeda, H., Nagano, T. and Ichimura, F., Pharm. Res. 1990, 7, 691; Hageluken, A., Grunbaum, L., Nurnberg, B., Harhammer, R., Schunack, W. and Seifert, R., Biochem. Pharmac., 1994, 47, 1789). The development of new systems for the delivery of these compounds could, therefore, significantly increase the therapeutic efficacies for the treatment of a wide variety of indications.
In this respect, one class of delivery vehicles that has shown great promise when used for the administration of pharmaceutical agents is fluorochemicals. During recent years, fluorochemicals have found wide ranging application in the medical field as therapeutic and diagnostic agents. The use of fluorochemicals to treat medical conditions is based, to a large extent, on the unique physical and chemical properties of these substances. In particular, the relatively low reactivity of fluorochemicals allows them to be combined with a wide variety of compounds without altering the properties of the incorporated agent. This relative inactivity, when coupled with other beneficial characteristics such as an ability to carry substantial amounts of oxygen, radioopaqueness for certain forms of radiation and low surface energies, have made fluorochemicals invaluable for a number of therapeutic and diagnostic applications.
For example, various fluorochemical emulsions have been used as oxygen carriers during medical procedures. Conventional oil-in-water emulsions, which may be infused directly into the blood stream, consist of a selected fluorochemical dispersed in the form of droplets in a continuous aqueous phase. Because of the high oxygen-carrying capacity of fluorochemicals, such emulsions are particularly useful as blood substitutes to provide oxygen to the vascular system. After administration of the emulsions, the oxygen dissolved in the dispersed fluorochemical phase is released into the blood. "Fluosol" (Green Cross Corp., Osaka, Japan), a formerly commercially available oil-in-water emulsion containing fluorochemicals, has been used as a gas carrier to oxygenate the myocardium during percutaneous transluminal coronary angioplasty (R. Naito, K. Yokoyama, Technical Information Series No. 5 and 7, 1981). Fluorochemicals have also been used as contrast enhancement media in radiological imaging by Long (U.S. Pat. No. 3,975,512) and in nuclear magnetic resonance imaging (U.S. Pat. No. 5,114,703). Other proposed medical uses include the treatment of cardiovascular and cerebrovascular diseases, coronary angioplasty, organ preservation and cancer therapy; diagnostic ultrasound imaging and veterinary therapy (Riess J. G., "Blood Compatible Materials and Devices": Perspective Towards the 21st Century, Technomics Publishing Co., Lancaster, Pa., Ch. 14, 1991; Riess, J. G., Vox. Sang., 61:225, 1991). Conventional direct fluorochemical emulsions have been described in, for example, EP-A-0 255 443, FR-A- 2 665 705, FR-A- 2 677 360, FR-A- 2 694 559, FR-A- 2 679 150, PCT/WO90/15807, EP-A-311473 and U.S. Pat. No. 3,975,512.
In addition to the aforementioned oil-in-water emulsion system, neat fluorochemicals and emulsions having a continuous fluorochemical phase have also been used in various medical applications. For instance, neat fluorochemicals are being evaluated for use in liquid ventilation applications. Currently one product, LiquiVent.TM. (Alliance Pharmaceutical Corp., San Diego, Calif.); is undergoing clinical trials for use in Respiratory Distress Syndrome (RDS). Such compositions could also be used in the treatment of premature infants with underdeveloped lungs. Another product, Imagent.RTM. GI, (Alliance Pharmaceutical Corp., San Diego, Calif.), an FDA approved diagnostic agent composed of a neat fluorochemical, is particularly useful for imaging the gastrointestinal (Imagent GI) tract. Fluorochemical liquids are also finding potential utility in eye surgery applications, such as the repositioning of posteriorly dislocated intraocular lenses and in the treatment of ocular ischemia (Lewis, H. and Sanchez, G., Ophthalmology, 1993, 100, 1055; Blair, N. P., Baker, D. S., Rhode J. P., and Solomon, M., Arch Ophthalmol, 1989, 107, 417).
While such applications are impressive, the ability to use fluorochemicals to reliably deliver effective amounts of pharmaceutical agents, either in conjunction with fluorochemical mediated therapy or in a separate dosing regime, would be of great benefit. The use of fluorochemical drug delivery vehicles would be particularly favorable for lipophilic drugs that are insoluble in aqueous solutions and present special problems in the aqueous physiological environment. For example, efficient pulmonary administration of pharmaceutical compounds, both lipophilic and hydrophilic, would be especially advantageous. Pulmonary administration of drugs constitutes a difficult problem because the introduction of compounds directly into the lungs cannot be effectively achieved by means of an aqueous solution or by fluorochemical emulsions wherein the continuous phase is also aqueous. Yet, as seen from the applications above, fluorochemicals may easily be introduced to the lung. Such direct administration is critical in the treatment of lung disease as poor vascular circulation of diseased portions of the lung reduces the effectiveness of intravenous drug delivery. In addition to treating pulmonary disorders, fluorochemical pharmaceutical formulations administered to the lung could also prove useful in the treatment and/or diagnosis of disorders such as RDS, impaired pulmonary circulation, cystic fibrosis and lung cancer. In addition to the pulmonary route of administration, fluorochemicals could advantageously be used for the administration of compounds via other routes such as topically, orally, intraperitoneally, or intraocularly.
Work in this area has shown that the pulmonary delivery of biological agents through the alveolar surface may be facilitated when accomplished in conjunction with liquid ventilation (Wolfson, M. R. and Shaffer, T. H., The FASEB J., 1990, 4, A1105), that is, using formulations having an oxygen rich fluorochemical continuous phase. The increased efficacy observed in compounds administered in conjunction with liquid ventilation to the impaired lung may be due to several factors, including the high spreading coefficients of some fluorochemicals on the pulmonary surface, an increase in alveolar surface area due to more effective lung inflation and the delivery of oxygen by the fluorochemical. Shaffer, et al., have also shown that pulmonary administration can increase the biological response of some drugs when compared to intravenous administration (Shaffer, T. H., Wolfson, M. R., Greenspan, J. S. and Rubenstein, S. D., Art. Cells, Blood Sub. & Immob. Biotech., 1994, 22, 315).
Yet, despite such successes, the administration of pharmaceutical compounds, particularly therapeutics designed for absorption by the body, is not without difficulties. A significant problem associated with conventional fluorochemical mediated drug delivery is that the large majority of drugs (lipophilic and hydrophilic) are insoluble in the fluorochemical phase. This may present a number of issues involving administration of the compound including stability, particle size, dose reliability, dispersion consistency and ultimately bioavailability. For example, the current method of pulmonary administration involves the preparation of a crude dispersion of the fluorochemical insoluble material and delivery by turbulent flow (Shaffer, T. H., Wolfson, M. R. and Clark, L. C., Pediatric Pulmonology, 1992, 14, 102). Yet, using this technique to deliver fluorochemical insoluble drugs (Shaffer et al., Art. Blood Subs. and Cells Immob. Biotech., 22:1994; Pediatr. Pulmonol., 14:102, 1992) resulted in non-homogenous, unreliable and irreproducible drug delivery due to the inefficient dispersion of the powdered agent in the fluorochemical phase. Moreover, while suitable delivery vehicles of comparable efficacy often exist for hydrophilic compounds, the choice for lipophilic agents is much smaller.
Drug suspensions in volatile chlorofluorocarbon propellants of the current art are often heterogeneous systems which usually require redispersion prior to use. Yet, obtaining a relatively homogeneous distribution of the pharmaceutical compound is not always easy in an "oily" fluorochemical. In addition, these formulations suffer from the disadvantage that they are prone to aggregation of the particles which, in the case of aerosol delivery, can result in clogging of the propellant system and inadequate delivery of the drug. Crystal growth of the suspensions via Ostwald ripening may also lead to particle size heterogeneity and can significantly reduce the shelf-life of the formulation. Another major problem with conventional dispersions, whether they are emulsions or suspensions, is particle coarsening. Coarsening may occur via several mechanisms such as flocculation, fusion, molecular diffusion, and coalescence. Over a relatively short period of time these processes can coarsen the formulation to the point where it is no longer usable. Comparable problems may occur in fluorochemical suspensions designed for other routes of administration such as through the gastrointestinal tract or ocular environment.
A further constraint on such conventional dispersions concerns the distribution of particle sizes. For oral administration, smaller drug particles or crystals, often on the order of 10 nm to 100 nm with large surface areas, are preferred due to their rapid diffusion for the delivery vehicle to the site of action. Unfortunately, it is generally not practical to produce particles having the optimal characteristics using conventional means such as airstreaming or grinding. Accordingly, many current formulations incorporate drug particulates having average particle diameters on the order of a few microns or more.
Several attempts have been made to solve these problems and provide efficient fluorochemical delivery vehicles. For instance, Evans et al. (Pharm. Res., 1991, 8, 629; U.S. Pat. 5,292,499; U.S. Pat. 5,230,884) and Jinks et al. (U.S. Pat. 4,814,161) disclose the use of highly volatile chlorofluorocarbon propellants stabilized by lipid surfactants to form micellar solutions for pulmonary drug delivery. Yet, neither teach the use of relatively nonvolatile fluorochemical liquid continuous media in these aerosol formulations. Rather they state that the inclusion of large proportions of high boiling components in these formulations is undesirable. Additionally, Evans et al. limit their disclosure to the solubilization of hydrophilic pharmaceutical compounds with no mention of incorporating hydrophobic compounds.
Accordingly, it is an object of the present invention to provide thermodynamically stable molecular solutions providing enhanced bioavailability for lipophilic pharmaceutical agents.
It is a further object of the present to provide surfactantless thermodynamically stable fluorochemical solutions for the administration of lipophilic pharmaceutical agents.
It is yet a further objective of the present invention to provide stable fluorochemical pharmaceutical solutions for use in partial liquid breathing therapy.
Still another objective to provide thermodynamically stable fluorochemical solutions incorporating lipophilic pharmaceutical agents having extended shelf-lives.